AIMS - This Phase II study aims to determine if a regimen of oral regorafenib has sufficient activity

and safety to warrant further evaluation in a phase III trial as a second or third line therapy for AOGC. The primary objective is progression-free survival, while secondary objectives include objective response rates, clinical benefit at 2 months, overall survival, safety, quality of life, and investigation of the prognostic/predictive role of circulating biomarkers.

BACKGROUND - After failure of first line treatment for AOGC, outcomes remain poor and treatment guidelines vary due to a lack of high level evidence showing clinically meaningful treatment benefit. Recently presented Phase III trials results demonstrated improved median survival for irinotecan vs. best supportive care (123 days vs 73 days; HR 0.42; p=0.023) (the AIO trial), and significant survival benefit for second line chemotherapy (SLC) (docetaxel or irinotecan) compared with BSC alone (5.1 months for SLC v 3.8 months for BSC; HR=0.63; 95% confidence interval, 0.47-0.86; p=0.004)(Park et al.Korea, 2011).

Studies of VEGF expression in gastric tumour tissue indicate a prognostic role with over-expression of vascular endothelial growth factor (VEGF) in tumour specimens from patients with AOGC, shown to be associated with rapid progression and poorer prognosis. High cVEGFR-1 levels have been associated with a poor overall survival in AOGC, and serum VEGF levels may identify patients more likely to benefit from anti-VEGF therapy (better outcome in “low” gp). A randomised Phase III trial of bevacizumab (anti-VEGF Monoclonal antibody) + chemotherapy (CX) in AOGC (AVAGAST) showed

significant improvement in the secondary efficacy endpoints of PFS (6.7 mo vs 5.3 mo; HR 0.80; p=0.0037) and ORR (46% vs 37%; p=0.0315) with bevacizumab but did not meet the primary endpoint of OS. This suggests that similar agents may have activity in AOGC. Regorafenib (BAY 73-4506) is an oral multi-kinase inhibitor targeting not only the angiogenic foci of bevacizumab (VEGFR, TIE-2), but also stromal (PDGFR-β) and oncogenic (RAF, RET and KIT) receptor tyrosine kinases. Two International Phase III studies of regorafinib have been reported in refractory GIST and refractory metastatic colorectal cancer both showing significant activity in the refractory setting.

STUDY DESIGN - INTEGRATE is a randomised phase II, double-blind, controlled trial with 2:1 (regorafenib:placebo) randomisation with stratification by lines of prior chemotherapy for advanced disease (1 vs. 2), and geographic region. 150 patients will be recruited from Australian, New Zealand, Canadian, and Asian sites over a 12-15 month recruitment period. Open label regorafenib will be offered to patients on the placebo arm post unblinding. Bayer AG will provide the study drug regorafenib and support for central costs via an untied educational grant.

STUDY PROGRESS - The protocol was approved by the NSW Cancer Institute Human Research Ethics committee on 16 July 2012 for public hospital sites in NSW, QLD, and VIC, and received regulatory approval in Canada 7 Dec 12, and in Korea 15 Jan 13.  Currently, 27/31 ANZ sites, 17/17 Canadian sites, and 7/7 Korean sites are active, and 95/150 patients have been enrolled to date. The 4 remaining ANZ sites are expected to activate in the next month, with recruitment expected to be completed by the end of 2013. An interim analysis for safety and futility is currently underway, with results to be reviewed by the IDSMC at an extraordinary meeting 16 Sept 13.

TRANSLATIONAL RESEARCH - Biological samples from patients will be used to identify biomarkers that are prognostic/predictive for study endpoints relating to survival, response, and safety.

Peripheral blood samples will be collected from trial patients at 3 specified timepoints: baseline, C2D1, C4D1 for this biomarker research (whole blood, serum and plasma). Planned biomarkers include; VEGF, sVEGFR-1, sVEGFR-2, sVEGFR-3, VEGF-A, VEGF-B, VEGF-C, VEGF-D; VEGF- 121 isoform, VEGF-165 isoform; IL8: tissue: IHC including Ger2, HIF, CA9.   Consent to donate archival tissue blocks for research is optional.